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Phenylbutyrate for STXBP1 Encephalopathy and SLC6A1 Neurodevelopmental Disorder

Sponsor
Weill Medical College of Cornell University (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT04937062
Collaborator
(none)
20
Enrollment
2
Locations
1
Arm
29
Anticipated Duration (Months)
10
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

STXBP1 Encephalopathy is a severe disease that can cause seizures and developmental delays in infants and children. It occurs when one copy of the STXBP1 gene has a mutation that causes the gene's protein to not work properly.

SLC6A1 neurodevelopmental disorder is characterized by developmental delay and often epilepsy. It occurs when one copy of the SLC6A1 gene has a mutation that causes the gene's protein to not work properly.

Both STXBP1 encephalopathy and SLC6A1 neurodevelopmental disorder cause symptom because there are not enough working proteins made by these genes. It is possible that a medication called phenylbutyrate may help the the remaining proteins work better. This study is to test if phenylbutyrate is safe and well tolerated in children with STXBP1 encephalopathy and SLC6A1 neurodevelopmental disorder.

Condition or Disease Intervention/Treatment Phase
  • Drug: Glycerol Phenylbutyrate 1100 MG/ML [Ravicti]
 Early Phase 1

Detailed Description

STXBP1 encephalopathy (STXBP1-E) is a devastating neurodevelopmental disorder that often begins in infancy. Intellectual disability is a core feature, often severe to profound. Nearly all have epilepsy (95% in the largest series). The epilepsy is clinically heterogeneous, and may present as a well-defined epilepsy syndrome (e.g., early infantile epileptic encephalopathy, infantile spasms, epilepsy of infancy migrating focal seizure, or Dravet syndrome) or as non-syndromic epilepsy. Seizures are refractory to medications in one third. Affected individuals may have autistic features (1 in 5), low tone, movement disorders (including ataxia and bruxism), abnormal EEGs (> 60% with focal or multifocal epileptiform discharges), and/or abnormal MRI brain imaging (atrophy, thin corpus callosum, delayed myelination). The clinical spectrum is broad -- some individuals are profoundly impaired with seizures that begin in the first days of life; whereas others may have a few seizures in late infancy and mild learning difficulties.

STXBP1 knockout mice show normal early brain assembly with subsequent degeneration, decreased neurite outgrowth, and completely abolished neurotransmitter release These mice die shortly after birth. Heterozygous STXBP1 mice are similar to wild-type, except they have abnormal behaviors during sleep (twitches and jumps) and EEG abnormalities. Thus, heterozygous STXBP1 mice recapitulate some aspects of the human disease, though they have neither seizures nor overt behavioral abnormalities. Human embryonic stem cell-derived neurons engineered for STXBP1 loss of function exhibit normal initial synaptogenesis, synapse size, and soma size; however, heterozygotes show decreased neurotransmitter release corresponding to decreased STXBP1 levels, while homozygous loss of function causes significant neural degeneration. Published experiments on neuronal lines derived from affected patients show decreased STXBP1 protein, STXBP1 protein mislocalization, and decreased neurite outgrowth. Early work in heterologous cell lines demonstrated STXBP1 mutations cause protein misfolding that leads to aggregation of the mutant protein with wild-type STXBP1.

In laboratory settings, stabilizing protein folding of the STXBP1 protein product with chemical chaperones rescued molecular and functional deficits in all tested models, using any of three chemical chaperones: sorbitol, trehalose, and 4-phenylbutyrate. Sorbitol and trehalose are sugars, and would be metabolized in the gut. 4-phenylbutyrate, however, is available as an FDA approved medication, either via sodium phenylbutyrate or glycerol phenylbutyrate. The glycerol formulation is better tolerated, thus this trial.

SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) begins in early childhood and is characterized by epilepsy (~91%, typically generalized) and developmental delay (~82%). The epilepsy is typically generalized (absence, atonic, myoclonic, generalized tonic-clonic) though is sometimes focal. Substantial minorities have an autism spectrum disorder, movement disorder, or problems with attention or aggression.

The protein product of SLC6A1 is GABA transporter protein type 1 (GAT-1), which is important for GABA homeostasis in the brain. Pathogenic mutations in SLC6A1 lead to loss of function and haploinsufficiency. Preliminary data suggests a dramatic impairment in GABA uptake in cells with homozygous variants in the GAT-1 protein, which improves with administration of phenylbutyrate.

The investigators are starting the investigation of phenylbutyrate for STXBP1-E and SLC6A1-NDD with this pilot study (i.e. Phase 1 study) in order to (a) understand safety and tolerability of the medication in children with STXBP1-E and SLC6A1-NDD, (b) understand the peak plasma concentrations in order to estimate CSF levels, and (c) generate exploratory information about clinical outcomes as a means to estimate effect sizes and pilot a battery of clinical testing for STXBP1-E and SLC6A1-NDD for future trials.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
20 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
This is a pilot, single treatment, multiple-dose, open label, study to be conducted in up to 10 children with STXBP1-E, and 10 with SLC6A1-NDDThis is a pilot, single treatment, multiple-dose, open label, study to be conducted in up to 10 children with STXBP1-E, and 10 with SLC6A1-NDD
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Glycerol Phenylbutyrate for STXBP1 Encephalopathy (STXBP1-E) and SLC6A1 Neurodevelopmental Disorder (SLC6A1-NDD)
Actual Study Start Date :
Mar 1, 2021
Anticipated Primary Completion Date :
Jul 31, 2022
Anticipated Study Completion Date :
Jul 31, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phenylbutyrate

Participants will be enrolled for 14 weeks, including 4 weeks of baseline information, 6 weeks of medication administration at the full dose, 2 weeks taper, and 2 weeks follow up. Note this is 8 weeks total of exposure to the medication for the duration of the trial. After clinical assessment by the investigator if deemed safe and appropriate, and requested by the caregiver, participants may continue to take phenylbutyrate for an additional 12 months, for additional monitoring of safety and tolerability.

Drug: Glycerol Phenylbutyrate 1100 MG/ML [Ravicti]
The investigator will rapidly titrate to a goal dose of 11.2 mL/m2 (12.4 g/m2) in three equally divided doses given enterally (by mouth or if necessary by g-tube) for 6 weeks, followed by a 2-week taper. This dose is consistent with the dosing guidelines in the FDA approved Medication Guide. Families will have the option to continue phenylbutyrate therapy at the goal dose of 11.2 mL/m2 (12.4 g/m2) in three equally divided doses given enterally for one additional year. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203284s005lbl.pdf).

Outcome Measures

Primary Outcome Measures

  1. Short Term Adverse events (i.e., safety) [14 weeks]

    The qualitative safety endpoint will describe any adverse events. It will include a description of the incidence, frequency, and severity of adverse events (including known side effects of the medication, changes in vital signs, EKG changes, EEG changes, increase in seizures, changes in clinical laboratory results, and/or changes in physical examination). We will monitor for these adverse events throughout the study, and measure them definitely at the end of the full 14 weeks of the protocol.

  2. Long Term Adverse events (i.e., safety) [1 year]

    The long term qualitative safety endpoint will describe any adverse events. It will include a description of the incidence, frequency, and severity of adverse events (including known side effects of the medication, changes in vital signs, EKG changes, EEG changes, increase in seizures, changes in clinical laboratory results, and/or changes in physical examination). We will monitor for these adverse events throughout the study, and measure them definitely at the end of additional 1 year if families opt to continue the study intervention.

  3. Percentage of doses taken by participants (i.e., tolerability) [12 weeks]

    The tolerability endpoint is quantitative and will measure medication compliance (i.e. what percentage of the doses are taken). The last dose of the medication is in week 12.

Secondary Outcome Measures

  1. Plasma concentration of phenylbutyrate [10 weeks]

    We will measure the plasma concentration of phenylbutyrate at the second inpatient admission (week 10), i.e., after 6 weeks of daily administration of the medication.

Eligibility Criteria

Criteria

Ages Eligible for Study:
2 Months to 17 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

  • Diagnosed with STXBP1-E or SLC6A1-NDD; confirmed by laboratory report (i.e., a genetic test with a pathogenic or likely pathogenic mutation of STXBP1 or SLC6A1-NDD and a clinical picture consistent with the disorder, as determined by the Investigator). Patients with the appropriate clinical picture, a de novo variant of uncertain significance in STXBP1 or SLC6A1-NDD will also be eligible for enrollment, at the discretion of the Investigator.

  • Is between 2 months and 17 years of age, inclusive.

  • For children with STXBP1-E, the child must have had at least one seizure in the past 30 days prior to enrollment. If there is high demand for the study and we have several subjects to choose, we will prefer to enroll children with a high number of seizures in the past month.

  • For SLC6A1-NDD, seizures occur later in the course (typically middle of 1st decade) and so seizures will not be an entry criteria.

  • Is in general good health, aside from neurological consequences of STXBP1-E or SLC6A1-NDD, as determined by having no concurrent medical illness, in the opinion of the site investigator, that places the subject at increased risk of adverse drug reactions or that will interfere with study follow-up.

  • Has normal laboratory test results (≤ 1.5 × upper limit of normal [ULN]) for serum aminotransferase (aspartate aminotransferas [AST] and alanine aminotransferase [ALT]) concentrations and ammonia at Screening.

  • Has normal renal function, with estimated glomerular filtration rate > 90 mL/minute/1.73 m2 at Screening (using the Chronic Kidney Disease Epidemiology Collaboration equation).

  • Has a platelet count > 150 × 103/μL at Screening.

  • Has a QT interval corrected with Fridericia's formula (QTcF) < 450 msec on the Screening EKG.

  • Parent or guardian is able to comprehend and willing to sign an informed consent form (ICF).

Exclusion Criteria:

  • Has participated in another investigational study within 30 days or 5 half-lives of the test drug's biologic activity (whichever is longer) before the first study drug dose.

  • Has a QT interval corrected with Fridericia's formula (QTcF) ≥ 450 msec on the Screening EKG.

  • Has an active medical illness that would preclude participation in the study (as determined by the Investigator).

  • Has a clinical laboratory evaluation outside of the test laboratory reference range, unless deemed not clinically significant by the Investigator and the Sponsor.

  • Is unable to comply with the study protocol.

  • Has poor venous access and/or cannot tolerate venipuncture.

  • Is pregnant

  • Is a female of child-bearing age (12 years old or older) and known to be sexually active (for example, as determined through a confidential HEADDSSS history), and not taking medication for contraception. This will be assessed confidentially as per good general pediatrics practice

  • Known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.

  • Taking alfentanil, quinidine, cyclosporine, valproic acid or probenecid (known interactions with phenylbutyrate). For subjects who had taken any of these medications in the past, the last dose must have been taken at least 1 week prior to enrollment into the study.

  • Inborn errors of beta oxidation.

  • Pancreatic insufficiency or intestinal malabsorption

Contacts and Locations

Locations

Site City State Country Postal Code
1 Children's Hospital Colorado Aurora Colorado United States 80045
2 Weill Cornell Medicine New York New York United States 10065

Sponsors and Collaborators

  • Weill Medical College of Cornell University

Investigators

  • Principal Investigator: Zachary Grinspan, MD, Weill Medical College of Cornell University

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:
Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT04937062
Other Study ID Numbers:
  • 19-10020997
First Posted:
Jun 23, 2021
Last Update Posted:
May 18, 2022
Last Verified:
May 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Keywords provided by Weill Medical College of Cornell University
phenylbutyrate
Additional relevant MeSH terms:
Brain Diseases
Neurodevelopmental Disorders
4-phenylbutyric acid
Glycerol

Study Results

No Results Posted as of May 18, 2022